Dataset Information

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

ABSTRACT:

Background

The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m² and (2) eGFR < 60 ml/min/1.73m². We aim to assess the efficacy and safety of alogliptin vs. placebo according to the renal function strata.

Methods

Cox-proportional hazard models with an interaction term by renal function strata were used. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke.

Results

Patient characteristics were balanced within each renal function strata. In total, 3946 patients were randomized within the eGFR ≥ 60 stratum, and 1434 patients within the eGFR < 60 stratum. The effect of alogliptin was modified by the renal function strata.

Primary outcome

eGFR ≥ 60 HR = 0.81, 95%CI, 0.65-0.99, and eGFR < 60 HR = 1.20, 95%CI, 0.95-1.53; interaction_p = 0.014. Cardiovascular death: eGFR ≥ 60 HR = 0.61, 95%CI, 0.42-0.88, and eGFR < 60 HR = 1.16, 95%CI, 0.82-1.65; interaction_p = 0.013. Non-fatal MI: eGFR ≥ 60 HR = 0.86, 95%CI, 0.66-1.13, and eGFR < 60 HR = 1.48, 95%CI, 1.07-2.06; interaction_p = 0.013.

Conclusions

Alogliptin may benefit patients with eGFR ≥ 60, but may be detrimental to patients with eGFR < 60 ml/min/1.73m². These hypothesis-generating findings require further validation to assess the potential benefit and risk of alogliptin across the renal function spectrum among patients with type 2 diabetes and a recent acute coronary syndrome.

Trial registration

ClinicalTrials.gov, NCT00968708.

SUBMITTER: Ferreira JP

PROVIDER: S-EPMC7271537 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

Ferreira João Pedro JP Mehta Cyrus C Sharma Abhinav A Nissen Steven E SE Rossignol Patrick P Zannad Faiez F

BMC medicine 20200604 1

<h4>Background</h4>The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m<sup>2</sup> and (2) eGFR < 60 ml/min/1.73m<sup>2</sup>. We ai ...[more]

PMID: 32493335

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Project description:BackgroundAcute Kidney Injury (AKI), a common complication of acute coronary syndromes (ACS), is associated with higher mortality and longer hospital stays. The role of cytokines and other mediators is unknown in AKI induced by an ACS (ACS-AKI), leading to several unanswered questions. The worsening of renal function is usually seen as a dichotomous phenomenon instead of a dynamic change, so evaluating changes of the renal function in time may provide valuable information in the ACS-AKI setting. The aim of this study was to explore inflammatory factors associated to de novo kidney injury induced by de novo cardiac injury secondary to ACS.MethodsOne hundred four consecutive patients with ACS were initially included on the time of admission to the Coronary Unit of the Instituto Nacional de Cardiología in Mexico City, from February to May 2016, before any invasive procedure, imaging study, diuretic or anti-platelet therapy. White blood count, hemoglobin, NT-ProBNP, troponin I, C-reactive protein, albumin, glucose, Na+, K+, blood urea nitrogen (BUN), total cholesterol, HDL, LDL, triglycerides, creatinine (Cr), endothelin-1 (ET-1), leukotriene-B4, matrix metalloproteinase-2 and -9, tissue inhibitor of metalloproteinases-1, resolvin-D1 (RvD1), lipoxin-A4 (LXA4), interleukin-1β, -6, -8, and -10 were measured. We finally enrolled 78 patients, and subsequently we identified 15 patients with ACS-AKI. Correlations were obtained by a Spearman rank test. Low-rank regression, splines regressions, and also protein-protein/chemical interactions and pathways analyses networks were performed.ResultsPositive correlations of ΔCr were found with BUN, admission Cr, GRACE score, IL-1β, IL-6, NT-ProBNP and age, and negative correlations with systolic blood pressure, mean-BP, diastolic-BP and LxA4. In the regression analyses IL-10 and RvD1 had positive non-linear associations with ΔCr. ET-1 had also a positive association. Significant non-linear associations were seen with NT-proBNP, admission Cr, BUN, Na+, K+, WBC, age, body mass index, GRACE, SBP, mean-BP and Hb.ConclusionInflammation and its components play an important role in the worsening of renal function in ACS. IL-10, ET-1, IL-1β, TnI, RvD1 and LxA4 represent mediators that might be associated with ACS-AKI. IL-6, ET-1, NT-ProBNP might represent crossroads for several physiopathological pathways involved in "de novo cardiac injury leading to de novo kidney injury".

Project description:Background Improved heart failure (HF) risk stratification after a recent acute coronary syndrome may identify those who can benefit from therapies that reduce HF risk. We aimed to identify clinical and biomarker predictors for expanded HF outcomes in patients with type 2 diabetes mellitus after recent acute coronary syndrome. Methods and Results The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial was a multicenter, non-inferiority, double-masked, placebo-controlled study which randomized 5380 patients with type 2 diabetes mellitus after recent acute coronary syndrome to alogliptin or placebo. Baseline biomarkers were measured in 5154 patients: NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity troponin I, adiponectin, growth-differentiation-factor-15, and galectin-3. Our primary outcome was cardiovascular) death, HF hospitalization, elevated NT-proBNP during follow-up, or loop diuretics initiation. The association between clinical variables, biomarkers, and outcomes were assessed using Cox regression models. In the study population, the median age was 61.0 years, 67.7% were men, and 28.0% had baseline HF (median follow-up was 18 months). In multivariable analyses, NT-proBNP had the strongest association with the primary outcome (per log2, hazard ratio 1.24; Wald χ2 67.4; P<0.0001) followed by a prior HF history (hazard ratio 1.42; Wald χ2 20.8; P<0.0001). A model with clinical variables and biomarkers allowed for risk prediction for expanded HF outcomes (C-statistic=0.72). Discrimination results were similar for cardiovascular death or HF hospitalization. Conclusions Among patients with type 2 diabetes mellitus after recent acute coronary syndrome, the use biomarkers such as N-terminal pro-B-type natriuretic peptide and clinical variables enables risk stratification for expanded HF outcomes. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT00968708.

Dataset Information

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

Background

Methods

Results

Primary outcome

Conclusions

Trial registration

Publications

Alogliptin after acute coronary syndrome in patients with type 2 diabetes: a renal function stratified analysis of the EXAMINE trial.

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